Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal sarcomas: feasibility, efficacy, toxicity, and long-term outcome.

PURPOSE: Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. METHODS: From 2000-2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m2 BSA/d3 q28 and ifosfamide 1.5 g/m2 BSA/d1­5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. RESULTS: The median follow-up time was 53 months (±56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (±10.1%) and 66.3% (±11.9%), distant metastasis-free survival was 67.2% (±9.7%) and 59.7% (±11.1%), and overall survival was 60.3% (±10.5%) and 60.3% (±10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. CONCLUSION: Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.

Operative results, sexual function and quality of life after gracilis muscle transposition in complex rectovaginal fistulas.

AIM: Successful treatment of complex rectovaginal fistulas (RVFs) continues to be a surgical challenge. Interposition of well-perfused tissue, such as gracilis muscle, is one treatment option. The aim of this study was to investigate the operative results, sexual function and quality of life after gracilis muscle transposition (GMT) in the authors' own group of patients. METHOD: The study included 19 women with RVF (mean age 48 years). The postoperative outcome was evaluated by a questionnaire and clinical examination. RESULTS: The postoperative follow-up period was 7 months to 3.5 years (mean 23 months). GMT led to primary healing of RVF in 10 (53%) patients. Recurrences were observed in nine (47%) patients with RVF, in four (44%) of whom healing was achieved as a result of further interventions. Following GMT, two complications (abscess formation) requiring revision occurred. Although 42% of the patients reported certain limitations following muscle removal, GMT is a procedure that has a positive influence on the healing rate (74%), quality of life, continence and patient satisfaction. CONCLUSION: GMT is a procedure that allows healing in the majority of patients with RVFs, and it should be considered especially in patients with recurrent fistulas, in whom a correlation between decreasing healing rates and the number of previous operations has been demonstrated.

Donor T-cell responses and disease progression patterns of multiple myeloma.

Donor T-cells transferred after allogeneic stem cell transplantation (alloSCT) can result in long-term disease control in myeloma by the graft-versus-myeloma (GvM) effect. However, T-cell therapy may show differential effectiveness against bone marrow (BM) infiltration and focal myeloma lesions resulting in different control and progression patterns. Outcomes of 43 myeloma patients who underwent T-cell-depleted alloSCT with scheduled donor lymphocyte infusion (DLI) were analyzed with respect to diffuse BM infiltration and focal progression. For comparison, 12 patients for whom a donor search was started but no alloSCT was performed, were analyzed. After DLI, complete disappearance of myeloma cells in BM occurred in 86% of evaluable patients. The probabilities of BM progression-free survival (PFS) at 2 years after start of donor search, alloSCT and DLI, were 17% (95% confidence interval 0-38%), 51% (36-66%), and 62% (44-80%) respectively. In contrast, the probabilities of focal PFS at 2 years after start of donor search, alloSCT and DLI, were 17% (0-38%), 30% (17-44%) and 28% (11-44%), respectively. Donor-derived T-cell responses effectively reduce BM infiltration, but not focal progression in myeloma, illustrating potent immunological responses in BM with only limited effect of T-cells on focal lesions.

[Branch duct intraductal papillary mucinous neoplasm - contra resection]. / Intraduktale papillär-muzinöse Neoplasie des Seitengangs­ Kontra Resektion.

Due to improvements in imaging modalities the diagnosis of branch duct intraductal papillary mucinous neoplasms (BD-IPMN) has been significantly increased in recent years. A BD-IPMN is frequently diagnosed as an incidental finding in asymptomatic patients. The optimal management of BD-IPMN is the subject of controversial discussions. Numerous studies have shown that an individualized therapeutic strategy with a follow-up observation of most BD-IPMNs is feasible and safe, considering age, comorbidities and patient preference. An accurate evaluation of BD-IPMN with a detailed anamnesis, high-resolution imaging techniques and endoscopic ultrasound is necessary. Symptomatic patients as well as patients with so-called high-risk stigmata should undergo resection. Asymptomatic patients with so-called worrisome features can either undergo surveillance or surgical resection, taking age and comorbidities into account. For BD-IPMN patients without high-risk stigmata and worrisome features and showing no symptoms, surveillance of the pancreatic lesion is the preferred approach. The high prevalence of BD-IPMN, limitations in differential diagnostics, an overestimation of the risk of malignancy due to an overrepresentation of symptomatic and suspected BD-IPMN in resected cohorts, an overestimated role of BD-IPMN as precursor lesions for pancreatic carcinoma and evidence of the safety of follow-up surveillance, underline the enormous importance of surveillance. Based on this and considering the background of a notable mortality and morbidity of pancreatic surgery, aggressive management with prophylactic surgical resection is not justified for all BD-IPMN, in particular for low-risk lesions.

[R1 resection for pancreatic carcinoma]. / R1-Resektion beim Pankreaskarzinom.

BACKGROUND: Surgery is the only potentially curative therapeutic approach in patients with pancreatic ductal adenocarcinoma (PDAC); however, achieving a negative (R0) resection margin is not always possible. OBJECTIVE: The impact of R1 resection margins on survival rates and treatment options (surgical and multimodal) for intraoperatively and postoperatively identified R1 resection margins. RESULTS: For intraoperatively diagnosed R1 resection margins, a re-resection (e.g. pancreas, main bile duct, stomach, superior mesenteric and portal vein) can be performed to achieve R0 resection margins. Arterial resections and the resection of additional organs are occasionally technically feasible and can be performed in an individual approach. New neoadjuvant and adjuvant treatment strategies have increased the rate of resectable PDAC and have improved the outcome of patients with R0/R1 resected PDACs. CONCLUSION: An R0 resection is the primary goal of surgery in patients with PDAC as R1 resections are correlated with a poor outcome.

[Alloplastic material in prolapse surgery : Indications and postoperative outcome of ventral rectopexy]. / Alloplastisches Material in der Prolapschirurgie : Indikation und postoperatives Outcome der ventralen Rektopexie.

BACKGROUND: In rectopexy the use of meshes provides stability by mechanical support as well as by the induction of scar formation; however, one of the problems of conventional methods of mesh rectopexy is that many patients postoperatively suffer from functional disorders, such as fecal incontinence and stool evacuation disorders. One reason is the damage of vegetative nerves following dorsal and lateral mobilization of the rectum, which is required for positioning of the mesh. In 2004 D'Hoore and Penninckx first described the method of ventral rectopexy, a new technique of mesh rectopexy which allows preservation of the autonomic nerves. OBJECTIVE: Does ventral rectopexy provide advantages regarding functional outcome, complications and recurrence rates? MATERIAL AND METHODS: A search was carried out in the databases PubMed and Medline for studies on ventral rectoplexy. Presentation and analysis of the current state of relevant studies relating to ventral rectopexy. RESULTS: Ventral rectopexy is characterized by a low complication rate and good functional results in terms of improvement of incontinence, constipation and stool evacuation disorders. The indications for ventral rectopexy are considered in patients with external prolapse of the rectum. Also in a well-selected patient population internal prolapse, rectocele as well as enterocele accompanied by obstructive defecation syndrome represent relative indications for ventral rectopexy. CONCLUSION: In order to obtain a valid assessment of the value of this procedure it is crucial to improve the current lack of evidence (level 3) by prospective randomized studies that compare ventral rectopexy with other surgical techniques and nonsurgical treatment options.

[Complication management following hemorrhoid operations]. / Komplikationsmanagement bei Hämorrhoidenoperationen.

BACKGROUND: Hemorrhoid operations are performed frequently in Germany. After the operation severe complications can occur that require appropriate management. OBJECTIVE: Presentation of current complications and suitable therapeutic options. MATERIAL AND METHODS: Data including operative procedures and complications that have been collected in an electronic online-based survey of all resident, affiliated and private practice German surgeons during the period from 1 December 2009 to 31 January 2010 are presented. A review of the current literature in a PubMed search is given. RESULTS: Stapled hemorrhoidopexy has several benefits during the early postoperative phase in comparison to conventional hemorrhoidectomy; however, patients should be informed about the possibility of postoperative defecation disorders, elevated recurrence and reoperation rates and rare life-threatening complications. CONCLUSION: The aim should be to keep risks at a low level by means of prevention, patient selection, careful analysis of indications and relevant expertise. In cases of complications early recognition and direct initiation of adequate treatment are crucial.

[Practical Implementation of the "Four-column Concept" in the Situation-Adjusted Therapy for Haemorrhoidal Disease in the Daily Routine of a Proctology Department]. / Praktische Anwendung des "4-Säulen-Konzepts" der situationsadaptierten Therapie des Hämorrhoidalleidens im alltäglichen Arbeitsfeld einer proktologischen Abteilung.

INTRODUCTION: In addition to the stage, several factors influence the treatment of haemorrhoids. The aim of this study was the elaboration of an individual therapy concept which is situation-adjusted. In this context, our own experience and approaches are presented. MATERIALS AND METHODS: In the Department of Coloproctology of the Prosper-Hospital Recklinghausen, from January 2009 to August 2012, 903 haemorrhoidectomies (2nd to 4th degree) have been performed. We report our results on the practical implementation of a situation-adjusted treatment of haemorrhoidal disease. In this context we present an overview of effective modifications of surgical techniques. Retrospectively the perioperative course and postoperative outcome were evaluated. RESULTS: Even in a collective with a large number of high-risk patients (26 %) respecting the "four columns" that constitute the fundament of a situation-adjusted treatment of haemorrhoids, high patient satisfaction and good outcome with low complication (7 %) and recurrence (0 %) rates could be attained. CONCLUSION: The "four columns" (findings of examination, therapeutic options, physician and patient) form the fundament of an effective treatment of haemorrhoidal disease without many complications and guarantee an individually tailored therapy for each patient.

[Situation-adjusted Treatment of Haemorrhoidal Disease]. / Situationsadaptierte Therapie des Hämorrhoidenleidens.

In addition to the stage several factors influence the treatment of haemorrhoids. The adequate treatment of haemorrhoids is not solely dependent on the stage, thus a situation-adapted therapy should be preferred. Advantages, disadvantages and specific characteristics of different therapy strategies in addition to potential complication risks have to be evaluated in order to obtain an effective and low-risk course. Also requests and personal living conditions of the patient as well as the expertise and experience of the physician have to be considered. A review of the current literature has been performed and a "four columns concept" has been developed that constitutes the fundament of a situation-adjusted treatment of haemorrhoids. The "four columns" that should be considered when therapy strategies are determined are composed of the following key factors: diagnostic findings, treatment alternatives, physician, and patient.

[Arterial reconstruction in pancreatic carcinoma ­demonstration of surgical techniques]. / Arterielle Rekonstruktion beim duktalen Pankreaskarzinom­ Darstellung chirurgischer Techniken.

INTRODUCTION: For a highly selected group of patients, a complete resection (R0) of a pancreatic carcinoma including arterial resection and reconstruction can represent an advantage in survival. The expertise of the surgeon in vascular and pancreatic surgery as well as the proficiency of the entire surgical and anaesthesiological team and the appropriate infrastructure of the hospital are prerequisites for the success of such complex operations. Proximal and distal of the tumour, sufficient lengths of the vessels are needed for the vascular anastomoses. In this video, the principles of arterial resection and reconstruction are shown in two patients with advanced pancreatic carcinoma. INDICATION: This procedure is indicated for locally advanced pancreatic carcinoma with arterial infiltration without distant metastasis after neoadjuvant therapy. PROCEDURE: The procedure involves 2 steps: 1. pancreatic head resection with resection of the common hepatic artery and end-to-end anastomosis of the hepatic artery and portal vein resection; 2. left pancreatic resection including splenectomy; resection of the celiac trunk, the superior mesenteric artery; reinsertion of the superior mesenteric artery into the aorta; end-to-end anastomosis of the common hepatic artery with the stump of the celiac trunk. CONCLUSION: Given the appropriate experience, technically demanding arterial resections and reconstructions in pancreatic carcinoma are feasible and can provide superior survival for the patient compared to palliative therapy.

[Recurrent colorectal liver metastases: who benefits from a second hepatic resection?]. / Rezidivlebermetastasen kolorektaler Karzinome: Wer profitiert von einer zweiten Leberresektion?

BACKGROUND: Hepatic recurrence is seen in approximately 40 % of patients undergoing hepatectomy for colorectal metastases. The authors assessed the benefit and the main prognostic factors for a second liver resection of recurrent colorectal metastases. METHODS: This study reports the experience with second liver resections for recurrent liver metastases at a German University Hospital. A total of 39 parameters from 60 patients were identified from a prospective database and analysed as to their influence on recurrence-free survival and overall survival. RESULTS: At a median follow-up of 26 months (range: 2-173 months) after second hepatic resection, recurrence-free survival at 3 and 5 years were 50 % and 37 %, respectively. The overall survival at three and five years were 61 % and 52 %, respectively. Recurrence was identified in 58.3 % of the patients. Recurrences involved exclusively the liver in 19 patients (31.6 %). By multivariate analysis (Cox proportional hazard model), a time interval between diagnosis of the liver metastases of less than 24 months after operation for colorectal primary carcinoma (HR: 6.47, p = 0.002), a CEA level of 4.0 ng/mL or more (HR: 3.48, p = 0.004) at the time of first liver metastases and a size of second liver metastases of 80 mm or more (HR: 4.73, p = 0.007) were independent prognostic factors for a reduced recurrence-free survival. A repeat recurrence of liver metastases without the option of curative resection was the only risk factor for overall survival after second hepatic resection (p = 0.009). In these cases, mortality risk was 4.51-fold, however, when the second liver recurrence was resectable, the mortality risk increased only 1.4-fold. CONCLUSIONS: Technically resectable recurrent colorectal hepatic metastases should be resected the same as the first metastases. Characteristics of the primary metastasis as well as parameters of the hepatic recurrence are shown to influence the prognosis of patients after resection of recurrent liver metastases. Repeat resection of colorectal liver metastases allows for improved survival in patients even after two previous liver operations.

Myeloablative T cell-depleted alloSCT with early sequential prophylactic donor lymphocyte infusion is an efficient and safe post-remission treatment for adult ALL.

The prognosis of adult patients with ALL remains unsatisfactory. AlloSCT is associated with a beneficial GVL response mediated by donor T cells. However, GVHD results in substantial mortality and long-term morbidity. T-cell depletion (TCD) of the graft reduces the severity of GVHD, but is associated with an increased relapse rate after alloSCT. Therefore, early sequential donor lymphocyte infusion (DLI) is likely to be necessary for a successful GVL reaction. Twenty-five adult ALL patients (10 Ph(+)ALL) were eligible for early DLI after initial disease control with myeloablative TCD-alloSCT in first CR (CR1), if active GVHD was absent at 3-6 months after alloSCT. Patients with a sibling donor or an unrelated donor were scheduled for 3.0 × 10(6) CD3(+) cells/kg or 1.5 × 10(6) CD3(+) cells/kg, respectively, at 6 months after alloSCT. Three patients died before evaluation (one early relapse). Five patients had active GVHD. Fourteen of the remaining seventeen patients received DLI (median time-to-DLI: 185 days). Overall, only 17% required long-term systemic immunosuppression for GVHD. With a median follow-up after TCD-alloSCT of 50 months, 2-year survival probability was 68% (95% confidence interval (CI) 49-87%). In conclusion, myeloablative TCD-alloSCT with early sequential DLI is an efficient and safe post-remission treatment for adult ALL patients in CR1.

[Surgical technique for pancreas transplantation]. / Die chirurgische Technik der Pankreastransplantation.

OBJECTIVE: The transplantation of a cadaveric donor pancreas represents a therapeutic option for the type 1 diabetic. A precondition is the proof of negative serum C-peptide after glucagon stimulation (< 0.02 ng/ml) as it is found in the typical patient with type 1 or a pancreoprive diabetes. The pancreas can be transplanted alone (PTA) or after a kidney (PAK), either following a preceding living related or cadaveric kidney transplantation. The majority of pancreata worldwide are transplanted simultaneously with a kidney (SPK) in stage 4 and 5 (eGFR < 29 ml/min) of chronic kidney disease. The beneficial effect of physiological glucose regulation on mortality, kidney failure and diabetic complications (cardiovascular, neuropathy, retinopathy) is well established. Patient survival rate at 1 year after transplantation is above 90 %, pancreas graft survival overall after 1 year is about 80 %. INDICATIONS: Type 1 diabetic patients with recurrent hypoglycemic episodes or major complications due to dysregulated glucose metabolism qualify for pancreas transplantation alone in case of a stable kidney function. Patients with chronic kidney disease stage 4 and 5 are candidates for SPK. PROCEDURE: Pancreatic transplantation into the right iliac fossa. CONCLUSION: Although technically demanding, pancreas transplantation is safely performable with a low periprocedural morbidity and mortality. Potential perioperative complications include inflammation, rejection or graft thrombosis. After a successful transplantation, long-term physiological glucose regulation can be achieved which results in a prolonged life expectancy and quality of life in type 1 diabetic patients.

Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets.

AIMS/HYPOTHESIS: Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. METHODS: C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. RESULTS: After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. CONCLUSIONS/INTERPRETATION: After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.

γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia.

Human cytomegalovirus (CMV) infections and relapse of disease remain major problems after allogeneic stem cell transplantation (allo-SCT), in particular in combination with CMV-negative donors or cordblood transplantations. Recent data suggest a paradoxical association between CMV reactivation after allo-SCT and reduced leukemic relapse. Given the potential of Vδ2-negative γδT cells to recognize CMV-infected cells and tumor cells, the molecular biology of distinct γδT-cell subsets expanding during CMV reactivation after allo-SCT was investigated. Vδ2(neg) γδT-cell expansions after CMV reactivation were observed not only with conventional but also cordblood donors. Expanded γδT cells were capable of recognizing both CMV-infected cells and primary leukemic blasts. CMV and leukemia reactivity were restricted to the same clonal population, whereas other Vδ2(neg) T cells interact with dendritic cells (DCs). Cloned Vδ1 T-cell receptors (TCRs) mediated leukemia reactivity and DC interactions, but surprisingly not CMV reactivity. Interestingly, CD8αα expression appeared to be a signature of γδT cells after CMV exposure. However, functionally, CD8αα was primarily important in combination with selected leukemia-reactive Vδ1 TCRs, demonstrating for the first time a co-stimulatory role of CD8αα for distinct γδTCRs. Based on these observations, we advocate the exploration of adoptive transfer of unmodified Vδ2(neg) γδT cells after allo-SCT to tackle CMV reactivation and residual leukemic blasts, as well as application of leukemia-reactive Vδ1 TCR-engineered T cells as alternative therapeutic tools.

[Anal sphincter repair in the treatment of anal incontinence - when and how to do it?]. / Anal Sphincter Repair zur Therapie der Stuhlinkontinenz - Wann und wie?

Anal incontinence is a disease of high prevalence. For many patients the disease causes severe stress and often results in social isolation. Whenever a sphincter lesion has been diagnosed by digital rectal examination and endosonographic access, anal sphincter reconstruction can be performed with the same results either in overlapping or in end-to-end suture technique. sing these procedures, in more than 60 % of patients the continence can be initially improved. However, benefit decreases after 5 years down to 40-50 %. The prognosis gets worse with increasing age and supplementary descending pelvic floor. Anal repair with reconstruction of internal and external sphincters is performed in neurogenic incontinence. This can be achieved by posterior or anterior anal repair (total pelvic floor repair). Nowadays these procedures are not common, due to unsuccessfulness. Instead, sacral nerve stimulation as a more expensive but less invasive method has displaced the anal repair on this indication. Interpretation of the published results remains delicate because of heterogenous evaluation criteria of postoperative outcome: subjective amelioration, postoperative satisfaction and quality of life, improvement of incontinence score or achievement of complete anal continence. However, it is proven that after immediate reconstruction of traumatic sphincter lesions the postoperative outcome is better than a two-step operation with primary ostomy.